Plasma proteomic profile reveals persistent immune activation in post-acute sequelae of SARS-CoV-2 infection

Plasma proteomic profiling of 92 individuals with Post-Acute Sequelae of SARS-CoV-2 infection (PASC), assessed a mean of 34 months after acute infection, revealed a distinct inflammatory signature. Using proximity extension assay technology, 358 proteins were quantified, identifying 26 differentially expressed proteins (DEPs) in PASC: 23 upregulated and 3 downregulated. The most upregulated proteins were Oncostatin M (OSM) and IL-1 receptor antagonist (IL1RN). Additional increases were observed in IL-6, IL-12B, IL-2, CCL22, CSF3, CSF1, and HLA-DRA, as well as proteins involved in tissue remodeling and angiogenesis such as ANGPTL2 and TGFA. Random forest analysis confirmed IL1RN, OSM, ANGPTL2, HLA-DRA, and CLEC4A as strong discriminators between patients and controls. Gene set enrichment analysis demonstrated activation of multiple immune pathways, including Inflammatory Response, TNF-α/NF-κB signaling, IL-6/JAK/STAT3, IL-2/STAT5, and Allograft Rejection, indicating persistent activation of innate and adaptive immunity. STRING network analysis highlighted a tightly connected cytokine-driven inflammatory module. Plasma spike protein levels did not differ between patients and controls, suggesting that PASC-related inflammation may persist independently of ongoing viral replication. Overall, the findings indicate a consistent low-grade inflammatory state in PASC without evidence for distinct biological subtypes.